This Section investigates the mechanism of action of excitatory amino acids in the vertebrate CNS, utilizing electrophysiological techniques. A fast perfusion system is used for concentration jump application of agonists and antagonists to nerve cells under voltage clamp. Responses to kainate show competitive block at equilibrium and slow activation kinetics in the presence of AMPA; this can be explained by a 5-state cyclic model of desensitization. Novel agonists at AMPA/kainate receptors, derived from willardiines, were found to vary > 10-fold in equilibrium efficacy, due to differences in the degree of desensitization. Drugs which reduce desensitization at AMPA/kainate receptors were tested for an action on excitatory synaptic transmission. Aniracetam slows the rate of decay and increases the amplitude of synaptic currents. EPSC variance analysis suggests a postsynaptic mechanism of action. In contrast the lectins WGA and Con-A decrease EPSC amplitude via a presynaptic effect on transmitter release. Structure-activity analysis of the kinetics of action of 17 NMDA receptor antagonists revealed that conformational restriction slows both association and dissociation rate constants. The ratio k off/k on was a good predictor of equilibrium potency. An increase in extracellular pH which allows greater ionization of the terminal PO3H2 group raises antagonist potency, suggesting that the doubly negative charged species is active at NMDA receptors.